Background Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. Methods A phantom with tubes of known diameters... Show moreBackground Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. Methods A phantom with tubes of known diameters and wall thickness was scanned for wall detectability, wall thickness, and contrast-to-noise ratio (CNR) on conventional and spectral black-blood (SBB) images. The clinical study included 34 stroke patients. Diagnostic certainty and conspicuity of normal/abnormal intracranial vessels using SBB were compared to conventional. Sensitivity/specifcity/accuracy of SBB and conventional were compared for plaque detectability. CNR of the wall/lumen and quantitative comparison of remodeling index, plaque burden, and eccentricity were obtained for SBB imaging and high-resolution magnetic resonance imaging (hrMRI). Results The phantom study showed improved detectability of tube walls using SBB (108/108, 100% versus conventional 81/108, 75%, p<0.001). CNRs were 75.9±62.6 (mean±standard deviation) for wall/lumen and 22.0±17.1 for wall/water using SBB and 26.4±15.3 and 101.6±62.5 using conventional. Clinical study demonstrated (i) improved certainty and conspicuity of the vessels using SBB versus conventional (certainty, median score 3 versus 0; conspicuity, median score 3 versus 1 (p<0.001)), (ii) improved sensitivity/specifcity/accuracy of plaque (≥1.0 mm) detectability (0.944/0.981/0.962 versus 0.239/0.743/0.495) (p<0.001), (iii) higher wall/lumen CNR of SBB of (78.3±50.4/79.3±96.7) versus hrMRI (18.9±8.4/24.1±14.1) (p<0.001), and (iv) excellent reproducibility of remodeling index, plaque burden, and eccentricity using SBB versus hrMRI (intraclass correlation coefcient 0.85–0.94). Conclusions SBB can enhance the detectability of intracranial plaques with an accuracy similar to that of hrMRI. Relevance statement This new spectral black-blood technique for the detection and characterization of intracranial vessel atherosclerotic disease could be a time-saving and cost-efective diagnostic step for clinical stroke patients. It may also facilitate prevention strategies for atherosclerosis. Show less
Wu, J.P.; Zou, Y.; Meng, X.; Fan, Z.Y.; Geest, R. van der; Cui, F.; ... ; Zhang, F. 2023
ObjectivesCarotid atherosclerosis plays an essential role in the occurrence of ischemic stroke. This study aimed to investigate whether a larger burden of napkin-ring sign (NRS) plaques on... Show moreObjectivesCarotid atherosclerosis plays an essential role in the occurrence of ischemic stroke. This study aimed to investigate whether a larger burden of napkin-ring sign (NRS) plaques on cervicocerebral computed tomography angiography (CTA) increased the risk of acute ischemic stroke (AIS).MethodsThis retrospective, single-center, cross-sectional study enrolled patients with NRS plaques identified in the subclavian arteries, brachiocephalic trunk, carotid arterial system, and vertebrobasilar circulation on contrast-enhanced cervicocerebral CTA. Patients were divided into AIS and non-AIS groups based on imaging within 12 h of symptom onset. Univariate and multivariate logistic regression analyses were performed to determine the risk factor of AIS occurrence.ResultsA total of 202 patients (66.72 years ± 8.97, 157 men) were evaluated. Plaques with NRS in each subject of the AIS group (N = 98) were significantly more prevalent than that in the control group (N = 104) (1.96 ± 1.17 vs 1.41 ± 0.62). In the AIS group, there were substantially more NRS plaques on the ipsilateral side than contralateral side (1.55 ± 0.90 vs. 0.41 ± 0.66). NRS located on the ipsilateral side of the AIS showed an area under the receiver curve (AUC) of 0.86 to identify ischemic stroke. NRS plaque amounts were an independent risk factor for AIS occurrence (odds ratio, 1.86) after adjusting for other factors.ConclusionsIncreased incidence of napkin-ring sign plaques on cervicocerebral CTA was positively associated with AIS occurrence, which could aid in detecting asymptomatic atherosclerotic patients at high risk of AIS in routine screening or emergency settings. Show less
Novel entities may pose risks to humans and the environment. The small particle size and relatively large surface area of micro- and nanoparticles (MNPs) make them capable of adsorbing other novel... Show moreNovel entities may pose risks to humans and the environment. The small particle size and relatively large surface area of micro- and nanoparticles (MNPs) make them capable of adsorbing other novel entities, leading to the formation of aggregated contamination. In this dissertation, we utilized advanced computational methods, such as molecular simulation, data mining, machine learning, and quantitative structure-activity relationship modeling. These methods were used to investigate the mechanisms of interaction between MNPs and other novel entities, the joint toxic action of MNPs and other novel entities, the factors affecting their joint toxicity to ecological species, as well as to quantitatively predict the interaction forces between MNPs and other novel entities, and the toxicity of their mixtures. The results indicate that understanding the mechanisms of interactions between novel entities and their modes of joint toxic action can provide an important theoretical basis for establishing effective risk assessment procedures to mitigate the effects of novel entities on ecosystems and human health. Furthermore, this dissertation provides important technical support and a practical basis for the quantitative prediction of the environmental behavior and toxicological effects of novel entities and their mixtures by applying various advanced in silico methods individually or in combination. Show less
The coronavirus disease-19 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rampant in the world and is a serious threat to global health. The SARS... Show moreThe coronavirus disease-19 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rampant in the world and is a serious threat to global health. The SARS-CoV-2 RNA has been detected in various environmental media, which speeds up the pace of the virus becoming a global biological pollutant. Because many engineered nanomaterials (ENMs) are capable of inducing anti-microbial activity, ENMs provide excellent solutions to overcome the virus pandemic, for instance by application as protective coatings, biosensors, or nano-agents. To tackle some mechanistic issues related to the impact of ENMs on SARS-CoV-2, we investigated the molecular interactions between carbon nanoparticles (CNPs) and a SARS-CoV-2 RNA fragment (i.e., a model molecule of frameshift stimulation element from the SARS-CoV-2 RNA genome) using molecular mechanics simulations. The interaction affinity between the CNPs and the SARS-CoV-2 RNA fragment increased in the order of fullerenes < graphenes < carbon nanotubes. Furthermore, we developed quantitative structure-activity relationship (QSAR) models to describe the interactions of 17 different types of CNPs from three dimensions with the SARS-CoV-2 RNA fragment. The QSAR models on the interaction energies of CNPs with the SARS-CoV-2 RNA fragment show high goodness-of-fit and robustness. Molecular weight, surface area, and the sum of degrees of every carbon atom were found to be the primary structural descriptors of CNPs determining the interactions. Our research not only offers a theoretical insight into the adsorption/separation and inactivation of SARS-CoV-2, but also allows to design novel ENMs which act efficiently on the genetic material RNA of SARS-CoV-2. This contributes to minimizing the challenge of time-consuming and labor-intensive virus experiments under high risk of infection, whilst meeting our precautionary demand for options to handle any new versions of the coronavirus that might emerge in the future. Show less
Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes.... Show moreRecombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1(-/-) mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34(+) cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID. Show less
Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly... Show moreDrug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds. Show less
This thesis mainly extends the theory of positive operators on Riesz spaces to a setting of pre-Riesz spaces. The theory of pre-Riesz space was established by M. van Haandel in 1993, which yields... Show moreThis thesis mainly extends the theory of positive operators on Riesz spaces to a setting of pre-Riesz spaces. The theory of pre-Riesz space was established by M. van Haandel in 1993, which yields that every directed Archimedean partially ordered vector space (pre-Riesz space) owns a vector lattice cover, that is, it can be embedded order densely into a Riesz space. Then this theory was developed by O. van Gaans and A. Kalauch during 1999-2016. Based on that, we study some properties of operators on pre-Riesz spaces, e.g. disjointness preserving operator, compact operator, disjointness preserving semigroup, local generator, dissipativity etc. on pre-Riesz spaces, which extends the classical operator theories on Riesz spaces and Banach lattices. Show less
